Immune Protection from Malaria: Age, Exposure Intensity, and the T Cell Response

疟疾的免疫保护：年龄、暴露强度和 T 细胞反应

• 批准号: 8473995
• 负责人: MARGARET E FEENEY
• 金额: $ 23.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8473995
• 关键词: 10 year old; Accounting; Activities of Daily Living; Acute; Africa; Age; Anopheles Genus; Antigens; Antimalarials; Biological Aging; Blood Volume; CD4 Positive T Lymphocytes; Cell physiology; Characteristics; Child; Childhood; Clinical; Cohort Studies; Culicidae; Cytokine Gene; Data; Development; Enrollment; Exposure to; Falciparum Malaria; Fever; Flow Cytometry; Frequencies; Gene Expression; Gene Expression Profile; Genome; Goals; Host Defense Mechanism; Household; Human; Immune; Immune response; Immunity; Immunology; In Vitro; Incidence; Individual; Infant; Infection; Interleukin-2; Life; Light; Malaria; Malaria Vaccines; Measurement; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Molecular Profiling; Morbidity - disease rate; Natural Immunity; Outcome; Phase; Plasmodium falciparum; Population; Predisposition; Regimen; Relative (related person); Research Infrastructure; Resistance; Resources; Risk; Role; Sampling; Shapes; Sporozoites; Surveillance Modeling; T cell response; T-Lymphocyte; Testing; Uganda; Vaccination; Vaccine Design; Vaccines; acquired immunity; age effect; base; cohort; cytokine; immune activation; insight; mortality; mouse model; population based; programs; prospective; response; surveillance study; transmission process; vaccination strategy; vaccine-induced immunity

Despite expanding control efforts, malaria still claims >1 million lives each year. A malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying immunity to malaria and a lack of reliable in vitro correlates of protection. Recently, experimental challenge models employing sporozoite vaccination have shed light on host defense mechanisms important for protective immunity, highlighting a critical role for malaria-specific T cells. These intriguing results suggest that careful study of the T cell response to malaria in cohorts of individuals with varying degrees of immunity may offer insight into the immune mechanisms required for protection, providing guidance for the rational design of vaccines. However, it is not known whether the mechanisms responsible for vaccine-induced immunity are identical to those underlying naturally acquired immunity. To date, population-based studies of antimalarial immunity among naturally exposed individuals have yielded no clear and consistent immune correlates of protection, but such efforts have been hindered by suboptimal measures of malaria incidence as well as the inability to control for confounding by exposure intensity and age. Using samples and data collected through an ongoing ICEMR cohort study, we have a unique opportunity to perform detailed analyses of malaria-specific T cell responses in a large cohort of children who will be followed longitudinally with careful measures of both malaria incidence and household-level exposure intensity. This cohort is based in a region of Uganda with exceptionally high year-round transmission intensity, and includes children 6 mos to 10 yrs of age, spanning the developmental period during which the natural acquisition of clinical immunity is normally observed. The proposed studies will utilize multiparameter flow cytometry, gene expression microarrays, and multiplex cytokine analysis to characterize the immune response to malaria and determine the relationship between this response and malaria incidence, controlling for both age and household-level exposure intensity. These studies will greatly enhance our understanding of the acquisition of natural immunity to malaria during childhood and the immune mechanisms responsible for protection.

尽管扩大了控制努力，但疟疾每年仍夺去100多万人的生命。疟疾疫苗急需 需要，但由于我们对机制的了解有限， 对疟疾的潜在免疫力以及缺乏可靠的体外保护相关物。最近，实验 采用子孢子接种的攻击模型揭示了宿主防御机制的重要性， 保护性免疫，突出了疟疾特异性T细胞的关键作用。这些有趣的结果表明 在免疫力不同的人群中仔细研究T细胞对疟疾的反应 可以提供深入了解保护所需的免疫机制，为合理的免疫机制提供指导。 疫苗的设计。然而，目前尚不清楚疫苗诱导的机制是否 免疫力与自然获得性免疫力相同。到目前为止，基于人口的研究 在自然接触疟疾的个体中，抗疟免疫没有产生明确和一致的免疫应答。 保护的相关因素，但这种努力受到疟疾发病率的次优措施的阻碍 以及无法控制暴露强度和年龄的混杂。使用样本和数据 通过正在进行的ICEMR队列研究收集，我们有一个独特的机会进行详细的 分析一个大型队列儿童的疟疾特异性T细胞应答， 对疟疾发病率和家庭一级的接触强度进行仔细测量。本队列 总部设在乌干达的一个地区，该地区全年的传播强度非常高， 6个月至10岁，跨越自然获得临床知识的发育期 通常会观察到免疫力。拟议的研究将利用多参数流式细胞术，基因， 表达微阵列和多重细胞因子分析来表征对疟疾的免疫应答， 确定这种反应与疟疾发病率之间的关系，控制年龄和 家庭一级的接触强度。这些研究将大大增进我们对收购的理解 儿童时期对疟疾的天然免疫力以及负责保护的免疫机制。